George Gee Jackson

First-exposure adaptive resistance to aminoglycoside antibiotics in vivo with meaning for optimal clinical use.

The first exposure of gram-negative bacilli to an aminoglycoside antibiotic in vitro induces a biphasic bactericidal response and adaptive drug resistance (G. L. Daikos, G. G. Jackson, V. T. Lolans, and D. M. Livermore, J. Infect. Dis. 162:414-420, 1990; G. G. Jackson, G. L. Daikos, and V. T. Lolans, J. Infect. Dis. 162:408-413, 1990). The therapeutic implications were examined in netilmicin treatment of a Pseudomonas aeruginosa infection of normal and neutropenic mice. For 2 h after the first dose, the bactericidal rates were rapid, 0.75, 1.0, and 1.5 log10 CFU/h with doses of 10, 30, and 60 mg/kg, respectively. Each twofold increase in dosage reduced the number of surviving bacteria fivefold. Between 2 and 6 h, the second-phase bactericidal rate was slow, less than or equal to 0.3 log10 CFU/h, regardless of the dose. In a multiple-dose regimen, the same amount of netilmicin given in one dose was 70 and 90% more effective than two or three doses, respectively. Doses calculated to keep the drug level in plasma above the MIC were less effective than regimens giving first exposure to a high drug concentration. Adaptive resistance occurred when doses were given more than 2 h after the start of treatment. Temporary survival of bacteremic neutropenic mice was 60 to 70% greater with a second dose at 2 h than after a longer interval. In a thigh infection of neutropenic mice treated every 2 h, doses 4, 6, and 8 h after the first one showed no bactericidal effect. A drug-free interval of 8 h (20 times the drug half-life) renewed bacterial susceptibility to drug action. The results in vivo confirm the biphasic bactericidal action and induction of adaptive resistance that characterized first exposure of gram-negative bacilli to aminoglycoside antibiotics. The phenomena have meaning for the optimum clinical use of aminoglycosides.

Alterations in outer membrane proteins of Pseudomonas aeruginosa associated with selective resistance to quinolones.

Electrophoresis of outer membrane proteins in three ciprofloxacin-resistant strains of Pseudomonas aeruginosa isolated during therapy and their in vitro revertants indicated that diminution or loss of a 31- to 32-kilodalton outer membrane protein correlated with resistance in two of the three isolates. Resistance was unstable and caused no cross-resistance with other antibiotics. Images

Viruses Causing Common Respiratory Infections in Man

Within the past two decades, many new viruses have been isolated and temporally associated with respiratory illness in humans. Initially, the taxonomic position of these viruses could not be assigned, and it was useful to assemble the known characteristics of each of them into a uniform format. With the acquisition of additional data, a more stable taxonomy of the viruses has been created. Nevertheless, the outline used in this manual was helpful for accumulating known and new data about these viruses and has served as a useful reference for

Long-term oral ciprofloxacin: Experience in the treatment of incurable infective endocarditis

Acute septic infective endocarditis caused by Pseudomonas aeruginosa, in two patients with conditions that made it incurable, was treated with long-term orally administered ciprofloxacin. Bacteremia and symptoms cleared, resulting in subjective well-being without cure for three and one half and 22 months, respectively. Large amounts of ciprofloxacin, 150 and 1,440 g, respectively, were given continuously without apparent adverse reactions. Blood isolates of P. aeruginosa after treatment had limited progression of resistance to ciprofloxacin. Use of orally administered ciprofloxacin provides new opportunities for the long-term treatment of serious infections with restricted risk of bacterial drug resistance and no appreciable side effects.

Topical enviroxime against rhinovirus infection.

Enviroxime, an inhibitor of rhinovirus replication, was studied in a double-blind, placebo-controlled trial with 99 volunteers. The efficacy of a nasal-spray formulation of enviroxime was tested as pretreatment or as postchallenge treatment for rhinovirus type 4 infection. In the regimens used, drug administration neither prevented infection nor reduced the frequency of specific colds. The mean concentration of enviroxime in nasal washes (12 h after a dose) differentiated two groups of responders. Those in whom the drug concentration exceeded 100 ng/ml had some benefits, although these were statistically insignificant.

Netilmicin: Clinical Efficacy, Tolerance, and Toxicity

Netilmicin, a new aminoglycoside antibiotic, has increased in vitro bactericidal activity against many strains of Enterobacteriaceae as compared to other aminoglycosides. It is a poor substrate for some of the common gentamicin-inactivating enzymes, and it has minimal toxicity in experimental animals. In 27 hospitalized patients, clinical cure was achieved in all, and the initial infecting organism persisted in only one. Therapeutic serum and urine levels were easily obtained in most patients. No ototoxicity was observed in two patients whose treatment required inordinately high serum levels and in whom other risk factors were present. Ototoxicity in 1 of 21 patients studied was unilateral, partially reversible, and not associated with high serum levels. Although nephrotoxicity occurred in 4 of 25 patients (16%), other host factors could have accounted for the toxicity in two patients. A new observation, not noted with other aminoglycoside antibiotics, was the elevation of serum alkaline phosphatase in 43% of the patients studied.

Intravenous and intraocular ganciclovir for CMV retinitis in patients with AIDS or chemotherapeutic immunosuppression.

The efficacy and toxicity of ganciclovir given by intravenous or intravenous plus intravitreal injection were studied in nine patients with cytomegalovirus (CMV) retinitis; seven with AIDS and two with drug induced immunodeficiency. Five patients had retinitis with macular involvement in six sighted eyes; six patients had only peripheral retinitis in seven eyes. In two patients (two eyes) with macular involvement intravenous plus intravitreal injection of ganciclovir preserved sight; intravenous infusion alone did not in four eyes of three other patients. In seven eyes (six patients) with peripheral retinitis vision was retained regardless of the route of ganciclovir treatment. Following intravenous ganciclovir drug levels in the vitreous fluid were 1.4-2.2 mmol/l, that is, 44 and 65% of the concomitant serum concentration. Clinically and at necropsy three eyes showed no evidence of toxicity from intravitreal injection of ganciclovir. All of five patients with AIDS who received intravenous ganciclovir for more than one week developed leucopenia. CMV retinitis of the macula may be benefited with minimal drug toxicity by intravitreal injection of ganciclovir. Treatment of peripheral CMV retinitis in patients with AIDS may be optional.

EVALUATION OF ANTIVIRAL DRUGS: THE EFFECT OF AMANTADINE ON INFLUENZA IN VOLUNTEERS*

Only a few of the vast and rapidly increasing number of antiviral agents being identified in laboratories throughout the world are considered for human trial. Such agents must act against viruses infectious to man and produce no adverse effects. The less toxic the drug, the more eagerly it is thrust into “field trial.” In the area of nonpneumonic viral disease of the respiratory tract, a multiplicity of infectious agents produces syndromes often so similar as to be clinically indistinguishable. For example, although fever is present in 90 per cent of adults with influenza, it is also a notable sign in 70 per cent of adenovirus infections in adults; constitutional malaise occurs in one-half to three-quarters of infections with the various respiratory viruses; nasal and pharyngeal symptoms are prominent in illness due to all the common respiratory viruses; bronchial symptoms are most common in influenza and adenovirus infections, and occur in more than half of the patients with infections by other common respiratory viruses.’ It is clear that a specific etiologic diagnosis of illness produced by these common respiratory viruses can rarely be made on clinical grounds alone. It is also well known that common viral respiratory diseases may continue to flourish during the time of specific epidemics. For these reasons, field trial of any antiviral agent directed against any specific viral disease of the respiratory tract is complicated and in some instances unreliable. Some of the disadvantages of field trial can be overcome by the use of volunteers. This group can be uniform as to age, state of health, geographical location, and occupation. By confinement, even the environment can be controlled and exposure to prevalent infecting agents prevented. In the absence of confinement, the season in which the upper respiratory infections are at a minimum and, particularly for our purposes, the season in which influenza is minimal, or hopefully absent, can be selected for the time of study. Using an infectious agent of known potency, the rate of infection is predictable. A live attenuated virus that produces infection with mild symptoms or no symptoms is a suitable agent for use in volunteers. A system by which antiviral agents can be tested in man with maximum safety is one in which infection is produced by an attenuated virus and.infection is measured by serological response.*J This system offers the advantages of a controlled infectious agent, a precise and specific indicator of infections, and the use of man as the test species. An example of the difficulties encountered in testing drugs against naturally acquired disease is the experiences with the drug, N‘, N’-anhydrobis (P-hydroxyethyl) biguanide hydrochloride, otherwise known as “ABOB.” This drug has been used in the treatment of influenza and other respiratory disease in studies involving large numbers of subjects and reported as an effective prophylaxis against influenza.4.5 On the other hand, in other large field trials, it has been found ineffecti~e.~.’ In the spring of 1961,2 330 male college students were subject for a study of this drug. They were divided into two groups according to the prechal-

Efficacy of Cinoxacin in Urinary Tract Infections

Cinoxacin, a new synthetic antibacterial agent with in vitro activity against all species of Enterobacteriaceae, was used in the treatment of urinary tract infections in 20 patients. The dose of cinoxacin was 250 mg orally every 6 h for 10 days. The etiological agents were Escherichia coli in fifteen, Klebsiella-Enterobacter in five, Proteus mirabilis in two, and Providencia in one. The minimal inhibitory concentration for these organisms ranged from 2 to 64 μg/ml. Eleven of the 20 patients had renal involvement by defined criteria, whereas the remaining nine were considered to have bladder bacilluria. The initial strain was eradicated during and immediately after treatment in 19 of 20 cases. At 6 weeks, 65% had sterile urine. Bactericidal urine levels of cinoxacin were obtained in all patients. No significant hematological, renal, hepatic, or gastroenterologic toxicity was noted. Cinoxacin appears to be a safe and useful drug in the treatment of urinary tract infections caused by Enterobacteriaceae. Images

FIELD STUDIES WITH AMANTADINE: ACCEPTABILITY AND PROTECTION

Amantadine hydrochloride (1-adamatanamine hydrochloride) is a synthetic organic amine compound reported to offer protection against influenza A2 infection.1-6 One action of the drug is to delay viral penetration of cells with subsequent inhibition of viral r e p l i ~ a t i o n . ~ Rimantadine (alpha-methyl1 -adamantanemethyl-amine hydrochloride) is a related compound with a similar mode of action and spectrum of virus inhibition.* Amantadine, when given before contact with the virus, has been shown to inhibit influenza virus infection in t issue cultures, mice and man. drugs, used in clinical studies in volunteers, have shown protection against experimental or natural influenza A2 i n f e ~ t i o n . ~ ~ When given at the t ime of pr after infection, amantadine has no protective effect.2* 9 Both